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Forms of Hypoxanthine Or, Through Interconversions, Guanine Or Adenine

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Forms of Hypoxanthine Or, Through Interconversions, Guanine Or Adenine 826 GENETICS: GOTS AND GOLLUB PROC. N. A. S. Summary.-The ribonucleic acids of isolated thymus nuclei can be separated into two distinct fractions, one of which probably represents ribonucleic acid of the nu- cleolus. Studies of the incorporation of orotic acid-6-C"4 and adenosine-8-C'4 into these RNA fractions in vitro show great differences in their metabolic activity and different susceptibilities to an inhibitor of RNA synthesis, the "nucleolar" RNA being by far the more active. It is a pleasure to acknowledge our indebtedness to Mr. Rudolf Meudt for his careful and expert technical assistance. * This research was supported in part by a grant (RG-4919 M&G) from the United States Public Health Service. I V. G. Allfrey, A. E. Mirsky, and S. Osawa, Nature, 176, 1042, 1955. 2 V. G. Allfrey, A. E. Mirsky, and S. Osawa, J. Gen. Physiol., 40, 451, 1957. 3 R. Logan and J. N. Davidson, Biochim. et Biophys. Acta, 24, 196, 1957. 4 S. Osawa, K. Takata, and Y. Hotta (in press). 6 J. M. Webb, J. Biol. Chem., 221, 635, 1956. 6 M. Bessis, in Traite de cytologie sanguine (Paris: Masson & Cie, 1954), p. 83. J. N. Davidson and R. M. S. Smellie. Biochem. J.. 52, 594, 1952. SEQUENTIAL BLOCKADE IN ADENINE BIOSYNTHESIS BY GENETIC LOSS OF AN APPARENT BIFUNCTIONAL DEACYLASE* By JOSEPH S. GOTS AND EDITH G. GOLLUB DEPARTMENT OF MICROBIOLOGY, SCHOOL OF MEDICINE, UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PENNSYLVANIA Communicated by D. Wright Wilson, July 3, 1957 Along the biosynthetic pathway to the purines of nucleic acids, inosinic acid occurs as a pivotal point in a bifurcation which leads to adenylic acid along one branch and to guanylic acid along the other: (B) r- Adenylic acid (AMP) (A) Inosinic acid (IMP) (C) L|_ * Guanylic acid (GMP) Bacterial mutations may result in genetic impairments at three locations with respect to the pivotal inosinic acid, thus yielding auxotrophs with three broad classes of nutritional response. A mutant which has lost the ability to synthesize inosinic acid de novo (block at A) can satisfy its growth requirements with various forms of hypoxanthine or, through interconversions, guanine or adenine. Such a mutant will be nondiscriminating in its choice of purines for growth and may accumulate various types of incomplete purines such as aminoimidazoles. When Downloaded by guest on September 28, 2021 VOL. 43,' 1957 GENETICS: GOTS AND GOLLUB 827 a block occurs after inosinic acid, specific requirements for adenine (block at B) or for guanine (block at C) will be manifested. The mutants to be considered here all belong to group B. Only adenine or its ribose derivatives will support their growth. The details of path B, the amina- tion of inosinic acid to form adenylic acid, have been provided by Carter and Cohen' and by Lieberman.2 Inosinic acid first combines with aspartic acid to form an intermediate, adenylosuccinic acid (AMP-S), which is then deacylated by a second enzyme to yield adenylic acid. Thus a specific growth requirement for adenine may occur if either of the two enzymes is lost by mutation. The culture fluids of thirteen mutants of Escherichia coli and Salmonella typhi- murium were examined for accumulations. Two of these accumulate a form of hypoxanthine, indicating a deficiency in the reaction which adds aspartic acid to inosinic acid. Ten of the thirteen accumulate a compound with a high absorp- tion in the ultraviolet (maximum at 267 mA), which at first was thought to be AMP-S but was subsequently identified as an aminoimidazole compound different from any of the aminoimidazole intermediates known to be accumulated by the nondiscriminating mutants of group A. Here, then, is an anomalous situation of a mutant which, because of its specific requirement for adenine, is apparently blocked at B, yet accumulates a type of compound which would be expected of mutants blocked at A. The paradox was clarified with the identification of the accumulated material as the ribotide of 5-amino-4-imidazole-N-succinylocarbox- amide (S-AICAR), an aminoimidazole which has been implicated as an inter- mediate in the biosynthesis of inosinic acid.3 S-AICAR, like AMP-S, represents an intermediate in an amination reaction formed by combination with aspartic acid. It serves as a means of introducing the amide nitrogen to 5-amino-4-imid- azolecarboxamide ribotide (AICAR), eventually to become the N1 of the purine ring. Deacylation of S-AICAR yields AICAR, the immediate precursor of inosinic acid. These reactions and their similarities to the formation and conversion of AMP-S are depicted in Figure 1. If the deacylation of both S-AICAR and AMP-S were under the control of a common enzyme, then the loss of this enzyme by mutation would create a block in the de novo synthesis of inosinic acid (path A) with the accumulation of S-AICAR and an additional block along branch B causing a specific deficiency in the formation of adenylic acid. The evidence to be pre- sented indicates that this is indeed the case. The findings have been described in a preliminary note, and similar conclusions have been obtained independently in other systems.5 Characteristics of the Mutant Strains.-The adenine-requiring mutants which accumulate the aminoimidazole include four strains of S. typhimurium (ad-3 and ad-12 obtained from T. Yura; strains 533-157 and 533-693 obtained from H. H. Plough) and six strains of E. coli which were isolated in this laboratory following ultraviolet irradiation of the, wild-type strain B and auxotrophic selection with penicillin. Strain B97 was selected as a typical representative of the group for further analyses. Maximum growth response is obtained with adenine or adenosine-5'- phosphate, poor growth with adenosine and adenosine-3 '-phosphate, and no growth with adenosine-2'-phosphate. If 0.1 per cent casein hydrolyzate is added to the medium, then maximal growth is obtained with all the above forms except Downloaded by guest on September 28, 2021 828 GENETICS: GOTS AND GOLLUB PROC. N. A. S. adenosine. Hypoxanthine, guanine, isoguanine, xanthine, and their ribose deriva- tives are completely inert. Maximal accumulation of the aminoimidazole can be detected in the culture fluids only under conditions of suboptimal growth, as obtained with a suboptimal supply of adenine. With an excess supply of adenine, accumulation is prevented. Rapid accumulation of the aminoimidazole can be obtained with nonproliferating cell suspensions under conditions which have been previously described.6 With glucose and ammonium chloride as the only sources of carbon and nitrogen, as HOOC-CH2, HOOC-CH C C HC-Nf C-NCN HN N. 1 CHa 11 k~CH N>H--cf H2N NR- C-NiA HaN R-P / H2N/ R-P HIN R-P A/R S-A/CAR A/CAR ,NH2 COOH- Ch-CH-COOH COOH-CH=CH-COOH ASPARTC ACID FUMAR/C ACID HOOC-CH-CH-COOH ?H \ NH NH2 t~~~oc\ //CI //~~~~~~~~~C\~~~~~~~~~~~~~~~~~~~~~~~~I F CH I~H -% HCs C-N HC C-N OC -N N R-P RN-PNRP /MP AMP-S AMP FIG. 1.-Similarities in formation and deacylation of AMP-S and S-AICAR. much as 0.5-1.0 Amole of the amine per milliliter may be formed in 2-3 hours. Aeration is required for optimal formation, and aspartic acid, glycine, and threonine stimulate production. Detection of S-AICAR.7-The accumulation of S-AICAR was first detected as a substance with a maximal absorption at 267 mu. Subsequent assay was made by a modification of the Bratton-Marshall8 test for diazotizable amines. This modification is based on a precise timing in the addition of the reagents and also serves to indicate that the accumulated amine is different from any of the known aminoimidazoles accumulated by other purine-requiring mutants and indeed is identical with S-AICAR. The test ordinarily calls for an interval of 5 minutes between the acidic diazotization with sodium nitrite, the removal of excess nitrite with ammonium sulfamate, and the eventual coupling with N-1-naphthylene- diamine dihydrochloride to produce a stable pigment. With most arylamines, such as AICA, the timing is not critical, since the diazonium complex is stable and can produce color with the coupling reagent even after a considerable delay. S-AICAR, however, apparently forms an unstable diazonium complex which rapidly decays at room temperature, so that color can be demonstrated only with rapid Downloaded by guest on September 28, 2021 VOL.V43, 19577,GENETICS: GOTS AND GOLLUB 829 coupling. No color is obtained with the usual delay of 5 minutes. The kinetics of coupling efficiency is that of a typical first-order decay reaction with a half- life of 36 seconds. The first indication that the accumulated amine and S-AICAR were indeed identical was based on their identical rates of loss of coupling efficiency. This is depicted in Figure 2. For assay purposes, the Bratton-Marshall test was standardized as follows: A sample of 2 ml., or an aliquot diluted to 2 ml., is acidified with 2 ml. of trichloro- acetic acid (7.5 per cent); 0.4 ml. of sodium nitrite (0.1 per cent) is then added and immediately mixed. At exactly 30 seconds, 0.4 ml. of ammonium sulfamate 100 50 - FIG. 2.-Loss of Bratton- >_ Marshall coupling efficiency of I 0 S-AICAR and of B97 amine. co _ Coupling delay refers to the time Z between diazotization and addi- SX1 - \ tion of coupling reagent (see I- - text) for S-AICAR (x) and B97 Z 5 \ amine (o). 0 0 1 2 3 4 5 6 7 COUPLING DELAY (MINUTES) (0.5 per cent) is added and again immediately mixed.
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